Bicyclic benzhydrylidene derivatives

ABSTRACT

Disclosed herein are bicyclic benzhydrylidene compounds which are non-steriodal hormonal agents useful, for example, in the inhibition of gestation in mammals.

260/247.2 R, 260/247.5 R, 260/247.7 R, 260/294 R, 260/294.3 R, 260/294.7R, 260/326.l6, 260/326.5 R, 260/345.8, 260/345.9, 260/475 R, 260/482 R,260/483 R, 260/485 R, 260/612 R, 260/613 R, 424/346, 424/341, 424/330,260/570 R I United States Patent 11 1 1111 3,760,007 Steinman [451 Sept.18, 1973 BlCYCLlC BENZHYDRYLIDENE [51] int. Cl. C07c 39/12 DERIVATIVES[58] Field of Search 260/570 R, M2, 619, [75] Inventor: Martin Steinman,Livingston, NJ. 260,619 A 619 R 619 D [73] Assignee: ScheringCorporation, Bloomfield, 5 R f r Cited NJ UNITED STATES PATENTS Filed: J11, 1970 3,237,200 2/1966 Barany et al 260/619 A x 3,287,397 11 1966OlSSOIl et al. 260/619 A x [211 App! 45535 3,406,209 10/1968 Barany etal 260/6l9 A Related US. Application Data {63] Continuation-impart OfSer. Nos. 873,112, om. 31, Primary Examiner-Bernard Helfin 1969,abandoned, and Ser. No. 714,027, March 18, Attorney-Stephen B. Coan,Raymond A. McDonald 1968, abandoned. and Bruce M. Eisen [52] 0.8. CI260/619 R, 260/619 A, 260/619 D, [57] ABSTRACT Disclosed herein arebicyclic benzhydrylidene compounds which are non-steriodal hormonalagents useful, for example, in the inhibition of gestation in mammals.

4 Claims, No Drawings BICYCLIC BENZHYDRYLIDENE DERTVATIVES Thisapplication is a continuation-in-part of my US. applications Ser. No.873,112, filed Oct. 31, 1969 and -Ser. No. 714,027, filed Mar. 18, 1968and both now where R represents hydrogen or lower alkyl; R representshydrogen, lower alkyl, chloro or fluoro; R represents hydrogen, hydroxy,lower alkyl, lower alkoxy, lower acyloxy, 2-dilower-alkylaminoethoxy, 2-piperidinoethoxy, 2-pyrrolidinoethoxy, 2- morpholinoethoxy ortetrahydropyran-2'-yloxy; R represents hydrogen, halogen or OR,; and Rrepresents hydrogen, lower alkyl, lower acyl, 2- diloweralkylaminoethyl,Z-piperidinoethyl, 2- pyrrolidinoethyl, 2-morpholinoethyl ortetrahydropyran-2-yl; n is either 0 or 1; x is either 3 or 4 and y is aninteger from 2 to 8.

The foregoing term lower alkyl (including the organic moiety of thelower alkyl group) includes straight or branch-chained radicals such asmethyl, ethyl, propyl, iso-propyl, n-butyl, tert.-butyl, n-amyl,iso-amyl, n-hexyl and the like. Methyl is the preferred lower alkylsubstituent and methoxy is the preferred lower alkoxy substituent. Thelower acyl radicals may be derived from such normally pharmaceuticallyacceptable acids as monobasic lower alkyl carboxylic acids such asacetic, propionic, butyric, isobutyric, valeric and caproic andpolybasic organic and inorganic acids such as succinic, maleic,tartaric, citric, carbonic, sulphuric and phosphoric acid. in thoseinstances wherein the acyl moiety represents a polybasic acid, theremaining free acid groups may be converted to the corresponding saltsand alkali metals, alkaline earth metals, ammonia or amines for example.

The carbobicyclic moiety which hereinafer may be referred to as Q can beattached to the benzhydrylidene moiety through any of its saturated ringcarbon atoms. The following groups are representative of Q (the firstnumeral designates the specific ring carbon atoms of the saturated ringwhich is attached to the benzhydrylidene moiety):

2 2-cis-bicyclo-[4.4.0l-decane; 3-trans-bicyclo-[4.4.0]- decane;3-cis-bicyclo-[4.4.0]-decane; 2-cis-bicyclo- [4.3.01-nonane;3-bicyclo-[4.4.01-nonane; 2-cisbicyclo-[3.3.0]-octane;2-trans-bicyclo-[4.4.0]-deca- 5(6)-ene; l-tetrahydronapthyl; andl-indanyl.

It is noted that the compounds of this invention can exist in severalstereoisomeric forms. In particular, the carbobicyclic moiety may giverise to cis and trans isomers involving the relative positioning of thering substituent e.g. cisand trans-decahydronaphthalene. It iscontemplated that all such isomers are embraced by this invention.

THe compounds of this invention can be conveniently prepared bydehydrating a benzhydrol of the formula:

O-FU ti or a benihydryl carbinol of the formula:

Egg; (LOH (III) wherein R is defined immediately below, the hydrortylgroup being attached to the O ring carbon atom which is bonded to thebenzhydryl moiety.

The carbinols designated by the structural formula ll wherein R is -ORare preferably prepared by reacting a bicyclic carboxy ester (IV) or anequivalent thereof with two moles of a p-substituted phenyl Grignardreagent (V) as follows:

-ooom 2R5MX Magnesium Complex (iv) (v) i Carblnol II Rio-Ox withmagnesium in a suitable form such as magnesium tumings in an ether, suchas diethyl ether or tetrahydrofuran. If K, were hydrogen or an acylgroup, the desired reactions would still proceed but would unnecessarily waste Grignard reagent through the reaction therewith.

The magnesium complex formed by carrying out Reaction Scheme A in themanner conventional for Grignard reactions is decomposed to form thedesired carbinol by adding, for example, water or dilute acids such asdilute hydrochloric acid or an aqueous solution of ammonium chloride.

Although the carbinol can be isolated and purified, such steps are notnecessary to enable it to be used in preparing the benzhydrylidenecompounds of this invention. It is sufficient to recover the carbinolfrom the aqueous reaction mixture by extraction with a suitable organicsolvent for the carbinol. Suitable solvents for this purpose includehigher aliphatic alcohols, ethers, ketones, hydrocarbons and halogenatedhydrocarbons, e.g. diethyl ether. The extract is then evaporated and theresidue is directly used as the starting material in preparing thebenzhydrylidene bicyclic compounds of the invention. If desired, thecarbinol may be isolated and purified in conventional manner, forinstance by recrystallization.

The carbinols represented by structural formulae 11 and 111 can bedehydrated to the corresponding benzhydrylidene compounds of thisinvention (1) by heating under atmospheric or reduced pressure. Thedehydration may be facilitated by the addition of various materials,such as sulphuric acid, phosphoric acid, phosphorous pentoxide inboiling benzene, alkali metal hydrogen sulphates, e.g. sodium andpotassium hydrogen sulphate, potassium pyrosulphate, iodine in xyleneand the like. The dehydration may also be carried out in aqueous toalcoholic alkali solutions, such as potassium or sodium hydroxidedissolved in water or lower alcohols having one to six carbon atoms orwith the corresponding lower potassium or sodium alkoxylates.

The desired benzhydrylidene bicyclic compounds of the invention thusformed may be isolated in any conventional manner, such as bydistillation at a pressure of 0.001 to 5 mm. of Hg and most preferablyat a pressure of from about 0.01 to about 0.2 mm. of Hg. The product maythen be further purified by reprecipitation or recrystallization.

The carbinols represented by the structural formula 11 can also beprepared by reacting a substituted benzophenone (V11) with ahalo-ring-substituted bicyclic compound (VIII) and two moles of areactive metal as follows: Reaction Scheme B:

(VII) (VIII) l Carbinol II wherein M is a reactive metal such as sodiumor lithium (butyl lithium) and R 0 and X have the above meanings. Thiscondensation reaction should be carried out in a solvent suitable forreactive metals such as liquid ammonia or ether.

The resulting complex can be destroyed by conventional procedures as,for example, the addition of ammonium chloride and then water followedby extraction with ether. The ether extract can then be poured in strongacid and the aqueous layer extracted with aqueous sodium chloride. Theresulting carbinol can be 2QMgX Magnesium Complex Carblnol II where in RQ and X has the above significance. The magnesium complex is worked upas described above.

The carbinols represented by the structural formula 111 may be preparedin analogous manner to that for carbinol 11. For example, by the methodof reaction Scheme B, the desired bicyclic ketone is reacted with thecorresponding diphenyl methyl halide or the diphenyl methane in thepresence of bimolar quantities of a reactive metal. These carbinols canbe worked up and dehydrated in the same manner described above forcarbinol 11.

As noted above, the various syntheses are more desirably conducted whenR is methyl or an equivalent blocking group rather than hydroxyl or acylgroups. The methoxy-substituted bcnzhydrylidene bicyclic compounds canbe converted into the corresponding hydroxy compounds by hydrolysisemploying, for example, potassium hydroxide at elevated temperature orboron trifluoride or aluminum trichloride at ambient temperature. Thecorresponding acyloxy compounds in turn may be prepared by acylating theparent hydroxy compounds employing in known manner conventionalacylating agents, e.g. acetic anhydride.

The invention is further illustrated by means of the following examples.

EXAMPLE l Preparation of 2 -(p,p'-dihydroxybenzhydry1idene)-cis-bicyclo-[4.4.01-decane and its diacetate'g. of

Add dropwise with vigorous agitation 1 1.6 g. of methylcis-bicyclo-[4.4.0l-decane-Z-carboxylate (0.06 mole) dissolved in ml. ofdry ether to a Grign ard reagent prepared from 3.8 g. of magnesium (0.16mole) and 26.2 g. of p-bromoanisole (0.14 mole) in 100 ml. of dry ether.Upon completion of the addition, stir the reaction mixture at roomtemperature for one hour and then reflux for one and a half hours withstirring and then cool and pour onto lON sulfuric acid and stir theresulting mixture overnight.

Separate the ether layer and extract three time with saturated aqueoussodium chloride, dry and the ether layer over anhydrous sodium sulfateand evaporate to dryness. This material distilled at 220C and 0.3 mm. Hgyields 13 g. of material which sets to a hard glass.

Stir 5.8 g. of this material,2-(p,pdimethoxybenzhydrylidene)-cis-bicyclo-[4.4.0]- decane (0.016 mole)together with 5.8 g. of potassium hydroxide pellets and 30 ml. oftriethylene glycol at 210C for four hours. Cool the mixture, pour ontowater, and extract with ether.Acidify the aqueous layer with 5Nhydrochloric acid and add ether. Wash the ethereal layer with asaturated aqueous solution of so dium chloride to neutral reaction andthen dry it over anhydrous sodium sulfate. Evaporate the solution todryness, dissolve the material in chloroform, treat with charcoal, andcrystallize to yield 4.8 g. or 2-(p,p'-dihydroxybenzhydrylidene)-cis-bicyclo-[4.4.0]- decane, m.p. 54C.

Add 3.0 g. (0.009 mole) of this material to 30 ml. of acetic anhydrideand add a drop of concentrated sulfuric acid. Heat the mixture on asteam bath for 30 minutes, cool to room temperature, and pour ontowater. Extract with ether two times, combine the ether layers andextract the latter two times with saturated aqueous sodium bicarbonatesolution. Dry the ether layer over anhydrous sodium sulfate andevaporate. The material is recrystallized from alcohol to yield 1.1 g.of thediacetate, mp. 111C.

EXAMPLE 2 Preparation of1-methyl-2-(p,pdihydroxybenzhydrylidene)-trans-bicyclo-[4.4.0]- decaneand its diacetate Add dropwise with vigorous agitation 8.4 of methyll-methyl-trans-bicyclo-[4.4.0l-decane-Z-carboxylate (0.04 mole)dissolved in 100 ml. of tetrahydrofuran to a Grignard reagent solutionprepared from 52.5 g. of p- (Z-tetrahydropyranyloxy)-bromobenzene (0.2mole) and 4.83 g. of magnesium (0.2 mole) in 500 ml. of tetrahydrofuranin the cold. Allow the reaction mixture to stand at room temperature for16 hours and then treat with a small amount of water. Remove theresulting gel by filtration. Add ether to the filtrate, wash the mixturewell with water and pour the ether layer onto lON sulfuric acid and stirovernight. Wash the ethereal layer with a saturated aqueous solution ofsodium chloride to neutral reaction and then dry it over anhydroussodium sultate. Evaporate the solution to dryness and recrystallize toobtain 1-methyl-2-(p,p'-dihydroxybenzhydrylidene)-trans-bicyclo-[4.4.0]- decane.

Add 2.3 g. (0.0066 mole) of this material to 12 ml. of acetic anhydrideand add a drop of concentrated sulfuric acid. Heat the mixture on asteam bath for 30 minutes, cool to room temperature, and pour ontowater.

Extract with ether two times, combine the ether layers and extract thelatter two times with saturated aqueous sodium bicarbonate solution. Drythe ether layer over anhydrous sodium sulfate and evaporate. Theresultant diacetate is dissolved in alcohol, treated with charcoal,

and allowed to crystallize.

EXAMPLE 3 Preparation of 3-(p,p'-dihydroxybenzhydrylidene)-cis-bicyclo-[3.3.0l-octane and its diacetate Prepare butyl Lithium at109C from 10.5 g. of lithium shot (1.5 moles) and 102.8 g. of butylbromide (0.75 mole) in 500 ml. of dry ether. Add to this reagentasolution of 114 g. of di-p-methoxyphenylmethane in 400 ml. of drytetrahydrofuran with stirring. After an hour at 10C and 62 g. ofcis-bicyclo-[3.3.0]-octan-3-one in 200 ml. of dry tetrahydrofuran andallow to warm to room temperature and stir overnight. Add water to themixture and extract with chlororform. Dry the organic layer overanhydrous sodium sulfate and evaporate to dryness.

To 20 g. of this carbinol in 200 ml. of dry pyridine, add 5.2 ml. ofthionyl chloride while cooling in an ice bath. Then heat under refluxfor 2 hours. Cool and add 50 ml. of 50 percent sodium hydroxide and heatunder reflux for 3/4 hour pour into ice water and extract with ether.Wash the ether layer with water to remove pyridine; dry and evaporatethe ether solution. Recrystallize from alcohol.

Stir the crystallized material, 3.7 g. of 3-(p,p'-dimethoxybenzhydrylidene)-cis-bicyclo-[3.3.01-octane (0.011 mole),together with 4 g. of potassium hydroxide pellets and 16 ml. oftriethylene glycol at 210C for four hours. Cool the mixture, pour ontowater, and extract with ether. Acidify the aqueous layer with 5Nhydrochloric acid and add ether. Wash the ethereal layer with asaturated aqueous solution of sodium chloride to neutral reaction andthey dry it over anhydrous sodium sulfate. Evaporate the solution todryness and recrystallize to obtain3-(p,p'-dihydroxybenzhydrylidene)-cisbicyclo-[3.3.0]-octane.

Add 2.0 g. (0.0066 mole) of this material to 12 ml. of acetic anhydrideand add a drop of concentrated sulfuric acid. Heat the mixture on asteam bath for 30 minutes, cool to room temperature, and pour ontowater. Extract with ether two times, combine the ether layers andextract the latter two times with saturated aqueous sodium bicarbonatesolution. Dry the ether over anhydrous sodium sulfate and evaporate. Theresultant diacetate is dissolved in alcohol, treated with charcoal, and

allowed to crystallize.

EXAMPLE 4 Preparation of 2-(p,p'dihydroxybenzhydrylidene)-trans-bicyclo-l4.4.01-decane and its diacetate Dissolve 2.51 g. ofsodium metal (0.11 mole) in liquid ammonia. Add 12.1 g. ofdi-pmethoxybenzophenone (0.05 mole) in ml. of ether. Stir for 15 minutesand add 8.6 g. of 2-chloro-transbicyclo-[4.4.0]-decane (0.05 mole) inether; stir a further four hours and allow to stand overnight. Carefullyadd 5.4 g. of ammonium chloride (0.1 mole) and allow the ammonia toevaporate. Treat the mixture with water and extract with ether. Pour theether layer onto ION sulfuric acid and stir overnight.

' Separate the ether layer and extract three times with saturatedaqueous sodium chloride, dry the other layer 'over anhydrous sodiumsulfate and evaporate the dryness. Recrystallize from alcohol.

Stir 7.2 g. of the crystallized material, 2-(p,pdimethoxybenzhydrylidene)-trans-bicyclo-[4.4.0]- decane (0.022 mole),together with 6 g. of potassium hydroxide pellets and 25 ml. oftriethylene glycol at 210C for four hours. Cool the mixture, pour ontowater, and extract with ether. Acidify the aqueous layer with 5Nhydrochloric acid and add ether. Wash the ethereal layer with asaturated aqueous solution of sodium chloride to neutral reaction andthen dry it over anhydrous sodium sulfate. Evaporate the solution todryness and recrystallize from ether-petroleum ether to 7 obtain2-(p,P'dihydroxybenzhydrylidene)- trans-bicyclo-[4.4.0]-decane, m.p.184186C.

Add 2 g. (0.0066 mole) of this material to 12 ml. of acetic anhydrideand add a drop of concentrated sulfuric acid. Heat the mixture on asteam bath for 30 minutes, cool to room temperature, and pour ontowater. Extract with ether two times, combine the ether layers andextract the latter two times with saturated aqueous sodium bicarbonatesolution. Dry the ether layer over anhydrous sodium sulfate andevaporate. The resultant diacetate is dissolved in alcohol, treated withcharcoal, evaporated to dryness, and crystallized from benzenehexane,m.p. 138140C.

In a manner similar to that of Example 4, other compounds of thisinvention may be prepared by substituting the correspondinghalo-ring-substituted compounds (IX) as for example:2-Chloro-cis-bicyclo-I4.4.0 ]-decane;3-Chloro-l-methyl-cis-bicyclo-[4.4.0l-decane;3-Bromo-7-methyl-trans-bicyclo-[4.4.01-decanc;2-Chloro-cis-bicyclo-[4.3.01-nonane;

. 3-Chloro-8-methyl-trans-bicyclo-[4.3.0]-nonane;

9-Bromo-cis-bicyclo-[4.3.01-nonane; and 2-Chloro-cis-bicyclo-[ 3 .3.01-octane.

EXAMPLE 5 Preparation of 1-(p,p'-dihydroxybenzhydrylidene)- 6-methoxy-l,2,3 ,4-tetrahydronaphthalene To a stirred suspension of 6.64 g. ofmagnesium turnings (0.273 mole) in 25 ml of dry tetrahydrofuran add 2 g.of p-(a-ethoxyethoxy)-bromobenzene and a crystal of iodine. Heat toinitiate reaction, then discontinue heating and add the remainder of thep-(aethoxyethoxy)-bromobenzene (66.9 g.; 0.273 mole total) in 50 ml. ofdry tetrahydrofuran dropwise at a rate to maintain reflux. Boil underreflux for one hour, cool, and add 18.7 g. of methyltetrahydro-l-naphthoate (0.091 mole) dropwise in 50 ml. of drytetrahydrofuran. Boil under reflux for 18 hours. I

Cool the reaction mixture and add 250 ml. of water. Collect theprecipitate on a bed of celite and discard; extract the filtrate withether, wash the ether layer with water and then saturated sodiumchloride solution and dry the ether layer over magnesium sulfate. Filterthe solution and evaporate the solvent. Take up the residue in 85 ml. of95 percent ethanol and 1 ml. of concentrated hydrochloric acid, boilunder reflux for 5 minutes,, cool and pour onto water. Extract withether, wash the ether layer with saturated sodium chloride solution anddry it over magnesium sulfate. Filter and concentrate to obtain crystalsof the title compound; 6.] g., m.p. 186-189C, tan needles andrecrystallize from ethanol (charcoal) to obtain an analytical sample,m.p. l91-2C.

Dissolve 1.5 g. of l-(6-methoxyl ,2,3 ,4-tetrahydronaphthyl)-p-hydroxyphenyl ketone (0.0053 mole) in 150 ml. oftetrahydrofuran. Add one drop of concentrated hydrochloric acid and 75ml. of ethyl vinyl ether. Boil under reflux for 3 days. Follow thereaction by thin layer chromatography on silica gel usingbenzene-hexane-ethylacetate (5:521) as eluent.

Cool the reaction micture, dilute with ether and extract with 2X25 ml.portions of percent sodium hydroxide; wash to neutrality with water, anddry over sodium sulfate. Filter, and evaporate to dryness to yield6-methoxy-1,2,3 ,4-'

a colorless oil (1.8g) which is used directly in the next step.

Prepare the Grignard reagent with 0.39 g. of magnesium turnings (0.016mole) and 3.92 g. of p-(aethoxyethoxy) bromobenzene (0.016 mole) and 50ml. of dry tetrahydrofuran. Add 1.83 g. of l-(6-methoxy-1,2,3,4-tetrahydronaphthyl)-p-(a-ethoxyethoxy) phenyl ketone (0.0052mole) in 10 ml. of dry tetrahydrofuran boil under reflux for 18 hours.

Cool to ambient temperature and add 10 ml. of water. Decant the liquidand dilute it with ether. Wash the ether solution with saturated sodiumchloride solution and dry over magnesium sulfate. Filter, evaporate todryness and add 30 m1. of 95 percent ethanol. Add 0.1 ml. ofconcentrated hydrochloric acid and boil under reflux for 5 minutes.Cool, pour onto water, extract with ether; then dry the ether solution(sodium sulfate) and evaporate to dryness.

Add ethanol and allow the solution to crystallize to yield 1-(p,p'-dihydroxybenzhydrylidene)-6-methoxy-1,2,3,4-tetrahydronaphthalene; 0.014 gram, m.p. 202 205C.

EXAMPLE 6 Preparation of l-(p-[N,N-diethylaminolethoxy-p'-hydroxy-benzhydrylidine)-6-(N,N- diethylamino)ethoxy-l,2,3,4-tetrahydro-naphthalene.

Heat under reflux for 4 hours 28.2 grams of l-(6- methoxyl,2,3,4-tetrahydronaphthyl)-phydroxyphenyl ketone (0.1 mole) in 200 ml.of acetic acid and 150 ml. of hydrobromic acid (48 percent). Pour thereaction product into 600 ml. ice-water, dry and crystallize fromethanol.

Add 26.8 grams (0.1 mole) of this product, l-(6- hydroxy-l ,2,3,4-tetrahydronaphthyl)-p-hydroxyphenyl ketone, dissolved in 100 ml.ethanol to 100 ml. of ethanol containing sodium ethoxide (prepared from9.2 grams of sodium). After cooling to 5C, add with stirring a solutionof 17.2 grams of N-(Za-chloroethyl) diethylamine hydrochloride (0.1mole) in 100 ml. ethanol. Heat the mixture under reflux with stirringfor 12 hours. Evaporate ethanol solution, add water and extract themixture with ether. Extract the ether layer 3 times with 2N hydrochloricacid. Basify the total acid extract with sodium hydroxide solution ndextract the product with ether. Dry the ether layer and evaporate toyield 1-(6-[N,N-diethylamino]ethoxy-1 ,2,3,4-tetrahydronaphthyl)-p-(N,N-diethylamino)ethoxyphenyl ketone.

Add to a stirred suspension of Mg turnings (2.43 grams: 0.1 mole) in 20ml. of dry tetrahydrofuran 2 grams of p-bromo-a-ethoxyethoxy benzene anda crystal of iodine. Heat the mixture to initiate the reaction andremove the heating source. Add 22.5 grams of the bromo compound (a totalof 0.1 mole) in 50 ml. of dry tetrahydrofuran dropwise to maintainreflux. Reflux for one hour and then add dropwise 23.3 grams ofl-(6-[N,N- ethylamino1ethoxy-l ,2,3 ,4-tetrahydronaphthyl)-p-(N,N-diethylamino)ethoxyphenol ketone (0.05 mole) in 50 ml. of drytetrahydrofuran and stir the mixture under reflux for 18 hours.

Cool the reaction mixture and add 200 ml. of water. After filteringthrough celite, add ether. Wash the ether layer with water, dry, andevaporate. Take up the residue in ml. of percent ethanol and 1 m1. ofconcentrated hydrochloric acid, reflux 5 minutes, cool and pour intowater. Add 2N hydrochloric acid to make the solution strongly acid andwash with ether. Basify the acid layer, wash with ether, and thenneutralize the alkaline layer and extract with ether. Dry the etherlayer and evaporate to yield the title compound. Prepare thedihydrochloride salt by dissolving the compound in ether and addingethereal hydrogen chloride. Collect the precipitate and dry.

EXAMPLE 7 Preparation ofl-(p-pyrrolidinylethoxy-p'-hydroxybenzhydrylidene)-6-hydroxy-l ,2,3,4-tetrahydronaphthalene.

Dissolve 26.8 grams ofl-(-hydroxy-l,2,3,4-tetrahydronaphthyl)-p-hydroxyphenyl ketone (0.1mole) in 300 ml. tetrahydrofuran. Add one drop of concentratedhydrochloric acid and 36 grams of ethyl vinyl ether. Reflux the mixturefor 3 days. Cool the reaction, dilute with ether and extract twice with25 ml. of 10 percent sodium hydroxide. Wash the ethereal extract withwater, dry and evaporate under reduced pressure to yield1-(6-a-ethoxyethoxy-l ,2,3,4-tetrahydronaphthyl)-p-a-ethoxyethoxy-phenyl ketone.

Add 2 grams of l-[2-(p-bromophenoxy)ethyl1- pyrrolidine and a crystal ofiodine to a stirred suspension of 2.43 grams of Mg turnings (0.1 mole)in 20 ml. of dry tetrahydrofuran. Heat the mixture to initiate thereaction and remove the heating source. Add dropwise the remainder ofthe bromo compound (total of 27 grams, 0.1 mole) in 50 ml. of drytetrahydrofuran to maintain reflux. After refluxing for one hour, adddropwise 23.3 grams of 1-(6-[N,N-diethylamino]ethoxy- 1,2,3,4-tetrahydronaphthyl)-p-(N,N-diethylamino)ethoxyphenyl ketone (0.05mole) in 50 ml. of dry tetrahydrofuran and stir the mixture under refluxfor 18 hours.

Cool the reaction and add 200 ml. of water. After filtering throughcelite, add ether. Wash the ether layer with water, dry, and evaporate.Take up the residue in 85 ml. of 95 percent ethanol and 1 ml. ofconcentrated hydrochloric acid, reflux for 5 minutes, cool and pour ontowater. Add 2N hydrochloric acid to make the solution strongly acid andwash with ether. Basify the acid layer and wash with ether and thenneutralize the alkaline layer and extract with ether. Dry the etherlayer and evaporate to yield the title compoundQPrepare thehydrochloride salt by dissolving the compound in ether and addingethereal hydrogen chloride. Collect the precipitate and dry.

EXAMPLE 8 Preparation of 1-(p-hydroxybenzhydrylidene)-6- methoxy-l,2,3,4-tetrahydronapthalene.

Prepare the Grignard reagent from 0.39 grams of Mg turnings (0.016mole), 2.51 grams of p-bromobenzene (0.016 mole) in 50 ml. of drytetrahydrofuran. Add 1.83 grams of 1-(6-methoxy-1,2,3,4-tetrahydronaphthyl)-p-a-ethoxyethoxyphenyl ketone (0.0053 mole) in 10ml. of water. Decant the liquid and dilute with ether, wash withsaturated sodium chloride and dry. Remove the solvent and add 30 ml. of95 percent ethanol. Add 0.1 ml. concentrated hydrochloric acid and boilthe mixture under reflux for 5 minutes. Cool the mixture, pour ontowater, and extract with ether. Dry the ether layer and concentrate toyield the title compound.

EXAMPLE 9 Preparation ofl-(p-[N,N-diethylamino]eth0xybenzhydrylidine)-6-(N,N-diethylamino)ethoxyl,2,3,4-tetrahydronaphthalene.v

Add 2 grams of p-bromo-benzene and a crystal of iodine to a stirredsuspension of Mg turnings (2.43 grams, 0.1 mole) in 20 ml. of drytetrahydrofuran. Heat the mixture to initiate the reaction and thenremove the heating source. Add dropwise the remainder of the bromocompound (total of 15.7 grams, 0.1 mole) in 50 ml. of drytetrahydrofuran to maintain reflux. After refluxing for one hour, adddropwise 23.3. grams of l-(6- [N,N-diethylamino]ethoxy-l ,2,3,4-tetrahydronaphthyl)-p-(N,N-diethylamino )ethoxyphenyl ketone (0.05 mole)in 50 ml. of dry tetrahydrofuran and stir the mixture under reflux for18 hours.

Cool the reaction and add 200 ml. of water. After filtering throughcelite, add ether. Wash the ether layer with water, dry and evaporate.Take up the residue in ml. of percent ethanol and 1 ml. of concentratedhydrochloric acid, reflux for 5 minutes, cool and pour onto water. Add2N hydrochloric acid to make the solution strongly acid and wash withether. Basify the acid layer and wash with ether and then neutralize thealkaline layer and extract with ether. Dry the ether layer and evaporateto yield the title compound. Prepare thedihydrochloride salt bydissolving the compound in ether and adding ethereal hydrogen chloride.Collect and dry the precipitate.

Similarly, by using analogous reactants in the abovedescribed syntheses,the other compounds of this invention may be prepared, as for example:

1-( p-piperidinoethoxy-benzhydrylidene)-3-methyl-5-fluoro-6-piperidinoethoxy 1,2,3,4-tetrahydronaphthalene;

l-(p-morpholinoethoxy-benzhydrylidene)-4-methyl- 6-methoxy-7-chloro-l,2,3,4-tetrahydronaphthalene;

4P:1612 511::QESEQ PFHZDXSEXEQWk9:. tetra ydropyan-Z'-yloxy-7-fluoro-1,2,3 ,4-tetrahydronaphthalene; and

2-(p-diethylaminoethoxy-p-chloro'benzhydrylidene)-5-chloro-1,2,3,4-tetrahydronaphthalene.

By employing the appropriate acylating agent, one may prepare theacylated compounds of Formula I as for example:2-(p,p'-dicaproyloxybenzhydrylidene)- cis-bicyclo-[4.4.0 ]-decane; l-(p-acetoxy-p'- isopropoxybenzhydrylidene)-5-methoxy-indane; anddisodium-(p,p' dihydroxybenzhydrylidene)-indane disulfate.

The bicyclic benzhydrylidene compounds of this invention are valuable asnon-steroidal hormonal agents. They tend to reduce the level of bloodcholesterol. They exhibit both estrogenic and anti-estrogenic activityand are particularly useful as anti-progestational agents. As usedherein anti-progestational is not meant to refer to the stage of thereproductive process during which the compounds exert their action.Rather the term anti-progestational as used herein refers to the grossresult, i.e. that fetal growth is inhibited. Although applicant does notwish his inventive concepts to be limited to his theory of thebiological mechanism or actions effected by the compounds of thisinvention, it appears that they inhibit ovulation, suppress theproduction of progesterone and/or prevent implantation or nidation.

The compounds of this invention are used by administering them in theform of a therapeutically effective quantity to the female mammal at atime between from several days prior to the expected onset of the sexualcycle, i.e. menses or estrus, until about one-tenth of the gestationperiod of the subject mammalian species has elapsed. After that time,the compounds of this invention are ineffective or are so rendered bythe chemical changes in the female body and/or fetus which have occuredin the interim.

The therapeutically effective quantity of the compounds of thisinvention may readily be ascertained by standard and well-knowntechniques in the art. One such laboratory technique is the 12-dayMating Test as described in The Journal of Endocrinology (1965), Vol.33, page 242. Therein the test compound, suspended in 1 ml. of a 1percent carboxymethylcellulose solution, is given by gavage for 11 daysto mature female rats of the same strain and approximate weight. Duringthis period they are housed with fertile males at a ratio of threefemales to one male. Control animals receive the suspending medium only.On the 12th day the number of pregnancies are determined by counting thenumber of nidation sites. The dosage is increased or decreased, asnecessary, to the minimal leval at which no pregnancies result. Thisdosage in milligrams per kilogram of body weight per day is referred toas the MPD i.e. the minimum protective dose for 100 percent of the testanimals.

Accordingly, from the foregoing test procedures as well as by standardlaboratory techniques as well as by comparison with knownanti-progestational" agents, the therapeutically effective dosage rangefor inhibiting gestation in mammals is readily determined. On theforegoing bases, a therapeutically effective dosage range for thecompounds of this invention is considered to be 0.1 75 mg/kg. of bodyweight. Dosages in the lower part of this range, i.e. 0.1 to 25 mg/kg.,are generally sufficient to inhibit gestation when taken beforeimplantation has occurred. Dosages in the upper part of this range, i.e.2 to 50 mg/kg., are generally necessary to inhibit gestation afterimplantation has occurred.

A suitable regimen consists of administering a single does of0.l 25mg/kg. ofa compound of this invention either (a) each of the five dayspreceding the expected onset of the sexual cycle, i.e. menses or estrus,or (b) each day for 5 to 7 days commencing 10 days after said onset. 1fpregnancy is suspected, a daily dose of 2-50 mg/kg. should beadministered once daily until pregnancy is no longer suspected or untilone-tenth of the gestation period is considered to have elapsed sincethe suspected day of preganancy. In each specific instance,

however, the attending diagnostician will, of course,

determine the dosage amount and frequency taking into account relatedhealth factors of the subject female.

The compounds of this invention may be administered as such or togetherwith suitable carriers which are pharmaceutically acceptable. A carrieris selected according to the route of administration to be used as wellas according to the physical properties of the compounds and standardpharmaceutical practice. In a preferred embodiment the compositions ofthis invention are administered orally, although patenteraladministration is also therapeutically effective and within the scope ofthis invention.

Typical formulations incorporating the anti progestational agents ofFormula 1 are described below. These formulations are intended to bemerely illustrative and no limitation is implied or intended.

EXAMPLE 6 250 Mg. Tablets Mix 250 mg. ofp,p'-dihydroxy-benzhydrylidene-2- cis-bicyclo[4.4.0]-decane, 50 mg. ofpowdered sugar, and mg. of corn starch and granulate with a 10% gelatinsolution. Dry the granulation and reduce to uniform granules fortableting. Add 45 mg. of corn starch (as disintegrant) and about 1percent of magnesium stearate (as lubricant). Compress the tablet to aweight of 450 mg. per tablet on a single punch or rotary machine, using7/16 inch punch.

EXAMPLE 7 lnjectable Suspension mixture, mg. per ml.

Sterilize the following ingredients separately: mg. ofp,p-diacetoxy-benzhydrylidene-2-cis-bicyclo- [4.4.0]-decane, 0.1 mg. ofTween 80 and q.s. of corn oil to make a final volume of one ml. Mixthese ingredients aseptically. Attain particle size by use of micronizedmaterial or by use of a ball mill, maintaining aseptic conditions. Thissuspension may be administered subcutaneously and intramuscularly.

Numerous variations of the above-described compositions and methodswithin the spirit of this invention will be apparent to one skilled inthe art.

1 claim:

1. A bicyclic benzhydrylidene compound of the formula wherein Rrepresents hydrogen or lower alkyl; R represents hydrogen, lower alkyl,chloro or fluoro; R represents hydrogen, halogen or hydroxy; x, y and nare integers selected such that the portion of the molecule having thestructure tetrahydronaphthalene.

2. A compound of claim 1, said compound being2-(p,p''-dihydroxybenzhydrylidene)-trans-bicyclo-(4.4.0)-decane.
 3. Acompound of claim 1, said compound being2-(p,p''-dihydroxybenzhydrylidene)-cis-bicyclo-(4.4.0)-decane.
 4. Acompound of claim 1, said compound being1-(p,p''-dihydroxybenzhydrylidene)-6-methoxy-1,2,3,4-tetrahydronaphthalene.